Safety and early biologic effects of phase 1 PERIO-01 trial of pressure-enabled drug delivery (PEDD) of TLR9 agonist SD-101 and immune checkpoint inhibition (ICI) in uveal melanoma metastatic to the liver (MUM).
Authors: Kamaneh Montazeri, Diwakar Davar, Cara L. Haymaker, Rahul Sheth, Joshua Kuban, Joshua Weintraub, Eric Wehrenberg-Klee, Paula M. Novelli, Carin F. Gonsalves, Robert D. Adamo, Anthony Lucci, Salyna Meas, Vanessa Nicole Sarli, Victor Gerardo Prieto, David A. Geller, Marlana M. Orloff, Richard D. Carvajal, Sapna Pradyuman Patel
Journal: Journal of Clinical Oncology (2023)

2521 Background: Delivery barriers due to intratumoral pressure and immunosuppression related to myeloid-derived suppressor cells (MDSC) in liver tumors have created challenges for immunotherapy. TLR9 agonists seem to improve response to ICI. PERIO-01 is a first-in-man trial of PEDD of SD-101 using hepatic arterial infusion (HAI) with ICI in MUM. Methods: PERIO-01 is an open-label phase 1 trial of SD-101 given by HAI in MUM (NCT04935229). The study consists of dose-escalation cohorts of SD-101 alone (Cohort A), with nivolumab (Cohort B), or nivolumab + ipilimumab (Cohort C). SD-101 is delivered over 2 cycles, with 3 weekly doses per cycle. Blood, liver metastasis (LM) and normal liver biopsies are collected for correlative studies. Results: At data cutoff, 33 patients were enrolled, 30 of whom received at least one dose of SD-101, 13 in Cohort A (2, 4, and 8 mg), 15 patients in Cohort B (2 mg and 4 mg) and 2 patients in Cohort C (2 mg). The median age was 63 years of equal gender. Only 3 patients were treatment-naïve and 2 were HLA-A*-02:01+ who received prior tebentafusp. Nine subjects had 4-7 LM and 4 had &gt; 10. The median index LM size was 4.7 cm. Only one patient experienced a grade ≥3 adverse event (AE) related to SD-101, which was increased liver enzymes. All AEs related to cytokine release syndrome have been low-grade with the most common being fever (9), chills (5), and dizziness (4). Treatment resulted in high liver drug levels (median at 2 mg = 1540 ng/g and 8 mg = 2325 ng/g, p = 0.035), with only transient exposure in the periphery ( &lt; 4 hours) and a maximum peak serum level of 554 mg/ml 30 minutes post-infusion. Increases in serum IL-18 and IFNγ were noted, with highest levels at 8 mg. Expansion of natural killer cells were detected in 9 of 10 patients from flow cytometry data peripherally. Monocytic MDSC levels were decreased in 5 of 5 patients on immunofluorescence, and NanoString analysis revealed decreases in ARG-1 and IDO-1 gene levels up to 100 days from initial treatment. Broad immunostimulatory gene expression changes were noted in tumor and normal liver following SD-101, including increases in IFNB1 and IL-9. Using the available samples from 13 patients, 7 of 10 had decrease in ctDNA, with complete clearance in 3, along with circulating tumor cell decreases in 6 of 13. In cohort B at 2 mg, 5 of 6 with available response data have stable disease with a median duration of disease control of 12 weeks (range = 7.5-24) at data cutoff. Conclusions: HAI of SD-101 has been well tolerated and associated with encouraging immunologic activity. Evidence of biologic effects at the lower doses of SD-101 with nivolumab is encouraging and enrollment with escalation continues in Cohorts B and C. Clinical trial information: NCT04935229 .